degradation, which is often seen during the development of human peptide hormones, has been addressed through natural selection of venom peptides.

There are about 700-800 species of venomous marine cone snails of the genus Conus. These feed on fish, molluscs and worms, and have developed a highly sophisticated venom apparatus. Conus magus and Conus consors are two closely- related fish-hunting species and are currently under investigation within the EU’s project ‘CONCO – the cone snail genome project for health’. Venoms have been poorly studied in the past. A few hundred toxic animal species have been investigated, and these studies have permitted only partial characterisation of about a thousand molecules. Venom components are typically classified according to their structural scaffold and/or their pharmacological target. In addition to small organic molecules, linear peptides and small proteins, the so-called ‘mini-proteins’ are the most promising venom bioactives.

Mini-proteins typically comprise from 10-70 amino acids and contain from one to five disulfide bonds. They are extremely resistant to proteases, and, in contrast to therapeutic proteins and antibodies, have low immunogenicity. Compounds isolated from venoms are usually very water-soluble. In addition, these mini-proteins have high selectivity towards important pharmaceutical targets, such as ion channel sub-types, receptors, transporters, enzymes or microorganisms. Their potency is usually in the low nM or pM range and therefore only limited development is required in order to obtain a viable drug candidate. Recent developments in the search for innovative leads have focused on the exploration of natural libraries and have included the large-scale preparation of pre-fractionated venoms ready-made for high-throughput screening. Results obtained from lead identification and structure-activity relationship studies can be combined with bioactivity-guided, structure-driven and biocomputing-assisted processes to speed

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Dr Ralph Schoenleber studied at the University of Basel and obtained a PhD in Chemistry in 2003 from the University’s Institute of Organic Chemistry, having worked under Professor Giese on ‘Coumarins as Photoactive Protecting Groups’. In 2003 he became a group leader at Bachem AG based in Bubendorf, Switzerland and in 2010 became director of the company’s Biochemistry and Process Research Department, with responsibility for process development, including scale-up strategies for all amounts of peptide products, and process research, where he was involved in custom synthesis and manufacture of products for the company’s catalogue business. Dr Schoenleber is a member of Bachem’s International Research Committee.

up the discovery process. In addition, lead selection and optimisation are supported by data mining, enabling the identification of analogous compounds in related venoms. Five venom-derived peptide drugs are already on the market (Table 1), and many more are currently undergoing preclinical and clinical development for the treatment of a range of diseases and conditions including cancer, pain, multiple sclerosis, stroke, allergies, diabetes and microbial infections.

A 150-litre reactor used in large-scale Fmoc solid phase peptide synthesis at Bachem.

Screening libraries agreement In September of last year, Bachem concluded an agreement with Atheris Laboratories to market Atheris’ Melusine® libraries for screening to identify potential new drugs. The libraries consist of natural products isolated from animal venoms. The agreement includes services to assist in the identification of the active ingredients and for the synthesis of individual compounds. These libraries have been fractionated to provide well-defined mixtures, with the main components being peptide toxins. Deconvolution and structural elucidation of hits and lead selection / optimisation can be performed at Atheris. Following identification of a hit from screening, Bachem can offer custom synthesis for lead compounds and provide support for clinical development of drug